Tuesday, 30 June 2015

Alemtuzumab, here I come: Top line results of the Ocrelizumab in relapsing MS studies

This morning, Roche announced the headline results of their Ocrelizumab in relapsing MS program (OPERA I and II). Here is their press release:

Numerous posts on this blog have highlighted the potential of this humanized version of Rituximab (check the "BartsMS essential off-label DMT list" in the left upper corner), an established drug to treat people with B cell lymphoma, for the treatment of people with MS. Ocrelizumab appears to be significantly better compared to interferon beta, however is it as good as alemtuzumab but without the significant risk of autoimmunity?

Rituximab is a chimeric antibody the variable region is mouse the constant region humanOcrelizumab is humanised so only the complementary determining region (target binding) are mouse and Ofatumumab is totally human and sat on a shelf...will it be moved now.

Functionally they are the same.....The question will be the price....they will want every 6 month dosing or an induction therapy.

Would this be useful in PPMS for the initial or any secondary inflammatory action?Or is this another purely RRMS drug, that the headline makers will state 'cure for ms' but forget those who have progressive disease

Then why are they waiting to file until 2016? I think they know the trial is positive for ppms and want to file on both rrms and ppms. Obviously reading tea leaves here but would think they would want to get to market asap otherwise.

I was thinking the other way round - they're probably starting to see that effects on ppms are either marginal, or not observable this far in. Otherwise, I'd expect to see some hint of positive data being collected. You'd think they'd want to back up the positive RRMS data with some suggestion that there was more good news to come, if they are presenting for shareholders. Look at how over-inflated the Biotin stuff was, before the data for it was released.

It blows my mind that incredibly powerful anti-inflammatories like Rituximab & Ocrelizumab don't seem to affect the low-grade inflammation typically associated with progression, yet something as benign as aspirin does seem to have an effect (even if only a subtle one).

Me too. The only thing with aspirin and ibuprofen is stomach problems. Even taking enteric-coated still causes bloating and constipation. But they do appear help with low-grade inflammation and also heat intolerance for me, and perhaps because of helping with low-grade inflammation and humidity, it also seems to help my cognition too. I don't take aspirin all the time, because of the stomach problems but enough to see a difference in cognition.

Likewise the importance is not when they announce the result the importance is when the regulators announce what they are going to do in terms of approval and the company will be working on this and I bet have been working on this waiting for the trial results. Remember time is money.

I guess there will be an investigators meeting when the neuros involved will be told of the result, is this going to be in Switzerland or US?

ProfG will know but is probably not allowed to say anything..The meeces are kept in the dark:-(

That the sole focus on T cells by the immunologists was misplaced and we've all been guilty of that to a greater or lesser extent over the years. If ocrelizumab is as effective as alemtuzumab at stopping relapses without the development of secondary autoimmunities, the alemtuzumab is finished. The same for Tysabri if PML isn't a problem.

Anon 7:28 - have a look at this link: http://multiple-sclerosis-research.blogspot.com/2015/04/aan-2015-embargo-lifted-early-on-optic.html

It's not an iron-clad guarantee that sodium channel blockers are the key to progressive MS, but the evidence thus far is pretty compelling, and it looks like the mice have done their homework. They make a pretty persuasive argument that this approach will likely save nerves.

This is all good and well but where next? They've proved that the drug has to be given early so why is there not more bejng done for those with the disease nowIs there further trials planned yet? When is this theory expected to be brought to the patients

MD, great science on your guys' part with the whole sodium channel blocker thing (seriously, well done). But I'm curious why you think that side effects would be worse for people with demyelination than for people without demyelination. Are you talking about the same side-effects as other folks, but just more likelihood of having them? Or totally different & new side-effects than those that have been seen in non-MS populations to date?

This is the reality the lamotrigine trial filed because 50% of people were not taking the drug. In health the sodium channels are concentrated at the nodes of ranvier which is the space between the myelin sheaths. When you have demyelination you get alot more channels because you need them to keep the nerve working, so blocking them can cause a number of problems including movement problems

Of note, I have a significant amount of experience with rituxan in off label in relapsing multiple sclerosis (> 200 patients), and I can tell you that mild infusion reactions are common, but serious infusion reactions are quite uncommon. Achieving undetectable b cell counts for 6+ months is common with rituxan. I doubt there would be any significant safety or efficacy improvements with ocrelizumab or ofatumumab, though ofatumumab is an anti CD19 agent. However, CD19 and CD20 counts are often identical, suggesting a very strong overlap (there are not many CD19+CD20- cells floating around). My experience concurs with what mouse doctor suggests-that rituxan is not effective in non-relapsing progressive multiple sclerosis which is radiologically silent. In the OLYMPUS trials (rituxan and PPMS), there was a signal in the post-hoc analysis were those who were < age 50 and had Gad+ lesions did better than placebo which is logical.

Ocreluzimab development was terminated in RA due to death due to infections. In RA is you fail to treat and you get damage you can replace a joint, but in MS you cannot replace a brain. So someone with MS will take more risks than someone with arthritis. Likewise if you have cancer that may kill you you will take more risks that someone with MS

PML Risk Infographic

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